RUXOLITINIB DISCONTINUATION SYNDROME: INCIDENCE, RISK FACTORS AND MANAGEMENT IN 242 PATIENTS WITH MYELOFIBROSIS
Author(s): ,
Francesca Palandri
Affiliations:
Institute of Hematology 'L. and A. Seràgnoli',Sant'Orsola-Malpighi University Hospital,Bologna,Italy
,
Giuseppe Alberto Palumbo
Affiliations:
Department of Scienze Mediche, Chirurgiche e Tecnologie Avanzate 'G.F. Ingrassia',University of Catania,Catania,Italy
,
Elena Maria Elli
Affiliations:
Hematology Division,San Gerardo Hospital, ASST Monza,Monza,Italy
,
Nicola Polverelli
Affiliations:
Unit of Blood Diseases and Stem Cells Transplantation, Department of Clinical and Experimental Sciences,University of Brescia, ASST Spedali Civili of Brescia,Brescia,Italy
,
Giulia Benevolo
Affiliations:
Division of Hematology,Città della Salute e della Scienza Hospital,Torino,Italy
,
Bruno Martino
Affiliations:
Division of Hematology,Azienda Ospedaliera 'Bianchi Melacrino Morelli',Reggio Calabria,Italy
,
Elisabetta Abruzzese
Affiliations:
Division of Hematology,Ospedale S. Eugenio,Roma,Italy
,
Mario Tiribelli
Affiliations:
Division of Hematology and BMT, Department of Medical Area,University of Udine,Udine,Italy
,
Alessia Tieghi
Affiliations:
Department of Hematology,Azienda USL - IRCCS di Reggio Emilia,Reggio Emilia,Italy
,
Roberto Latagliata
Affiliations:
Division of Cellular Biotechnologies and Hematology,University Sapienza,Roma,Italy
,
Francesco Cavazzini
Affiliations:
Division of Hematology,University of Ferrara,Ferrara,Italy
,
Micaela Bergamaschi
Affiliations:
Clinic of Hematology, Department of Internal Medicine (DiMI),IRCCS AOU San Martino-IST,Genova,Italy
,
Gianni Binotto
Affiliations:
Unit of Hematology and Clinical Immunology,University of Padova,Padova,Italy
,
Monica Crugnola
Affiliations:
Haematology and BMT Centre,Azienda Ospedaliero-Universitaria di Parma,Parma,Italy
,
Alessandro Isidori
Affiliations:
Hematology and Stem Cell Transplant Center,AORMN Hospital,Pesaro,Italy
,
Giovanni Caocci
Affiliations:
Hematology Unit, Department of Medical Sciences and Public Health,University of Cagliari,Cagliari,Italy
,
Florian Heidel
Affiliations:
Internal Medicine II, Hematology and Oncology,Friedrich-Schiller-University Medical Center,Jena,Germany
,
Novella Pugliese
Affiliations:
Department of Medicine and Surgery, Hematology and Hematopoietic Stem Cell Transplant Center,University of Naples Federico II,Napoli,Italy
,
Costanza Bosi
Affiliations:
Division of Hematology,AUSL di Piacenza,Piacenza,Italy
,
Daniela Bartoletti
Affiliations:
Institute of Hematology 'L. and A. Seràgnoli',Sant'Orsola-Malpighi University Hospital,Bologna,Italy
,
Giuseppe Auteri
Affiliations:
Institute of Hematology 'L. and A. Seràgnoli',Sant'Orsola-Malpighi University Hospital,Bologna,Italy
,
Daniele Cattaneo
Affiliations:
Hematology Division,Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico,Milano,Italy
,
Luigi Scaffidi
Affiliations:
Department of Medicine, Section of Hematology,University of Verona,Verona,Italy
,
Malgorzata Monica Trawinska
Affiliations:
Division of Hematology,Ospedale S. Eugenio,Roma,Italy
,
Rossella Stella
Affiliations:
Division of Hematology and BMT, Department of Medical Area,University of Udine,Udine,Italy
,
Fiorella Ciantia
Affiliations:
Division of Hematology,AOU Policlinico V. Emanuele, University of Catania,Catania,Italy
,
Fabrizio Pane
Affiliations:
Department of Medicine and Surgery, Hematology and Hematopoietic Stem Cell Transplant Center,University of Naples Federico II,Napoli,Italy
,
Antonio Cuneo
Affiliations:
Division of Hematology,University of Ferrara,Ferrara,Italy
,
Mauro Krampera
Affiliations:
Department of Medicine, Section of Hematology,University of Verona,Verona,Italy
,
Gianpietro Semenzato
Affiliations:
Unit of Hematology and Clinical Immunology,University of Padova,Padova,Italy
,
Roberto Massimo Lemoli
Affiliations:
Clinic of Hematology, Department of Internal Medicine (DiMI),IRCCS AOU San Martino-IST,Genova,Italy
,
Alessandra Iurlo
Affiliations:
Hematology Division,Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico,Milano,Italy
,
Massimo Breccia
Affiliations:
Division of Cellular Biotechnologies and Hematology,University Sapienza,Roma,Italy
,
Nicola Vianelli
Affiliations:
Institute of Hematology 'L. and A. Seràgnoli',Sant'Orsola-Malpighi University Hospital,Bologna,Italy
,
Michele Cavo
Affiliations:
Institute of Hematology 'L. and A. Seràgnoli',Sant'Orsola-Malpighi University Hospital,Bologna,Italy
Massimiliano Bonifacio
Affiliations:
Department of Medicine, Section of Hematology,University of Verona,Verona,Italy
(Abstract release date: 05/14/20) EHA Library. Palandri F. 06/12/20; 295037; S217
Francesca Palandri
Francesca Palandri
Contributions
Abstract

Abstract: S217

Type: Oral Presentation

Session title: Novel therapies and pitfalls in MPN

Background
Ruxolitinib (RUX) is effective in controlling myelofibrosis (MF)-related splenomegaly and symptoms by JAK1/JAK2 inhibition. In the phase I/II study, 11% of the patients (pts) experienced a RUX discontinuation syndrome (RDS), a wide range of adverse events (AEs) attributed to a rebound cytokine storm.

Aims

To investigate in a real-world contest: 1) incidence, timing and severity of RDS; 2) type of prevention strategies; 3) risk factors associated with RDS.

Methods

Overall, 700 MF pts were treated with RUX in 20 European Hematology Centers. Spleen (SR) and symptoms (SyR) responses were evaluated according to IWG-MRT criteria.

Results

After a median follow-up from RUX start of 36.3 mos, 242 (34.6%) pts stopped RUX and survived >30 days after discontinuation. At RUX start, characteristics of these 242 pts were: median age 67y (24-88); males 59.9%; PMF 59.9%; median Hb 10 g/dl; median PLT/WBC: 211/10.2 x109/l. At any time, 43.8% and 80.2% of pts achieved a SR or a SyR.

Causes of RUX stop were: RUX failure (60.6%: lack/loss of SR/SyR or leukemic transformation); AEs (28.6%; hematological AEs: 20.7%); other causes (10.8%). At the time of decision to stop RUX, daily dose (mg BID) was: 5, 10, 15 or 20 in 46.3%, 21.9%, 16.5% and 15.3% of pts.

An active strategy to prevent RDS was performed in 101 (41.7%) pts, specifically: RUX taper alone (44 pts); RUX taper in combination with prednisone (PDN) ± hydroxyurea (HU) (32 pts); PDN ± HU without tapering (25 pts). Median duration of tapering was 20 days (2-90). Median PDN dose was 12.5 mg/d, with a median exposure of 29 days (10-255); HU was used at a median dose of 1 g/d for a median of 60 days (4-210). In the remaining 141 (58.2%) pts, RUX was quickly discontinued without any specific intervention.

Overall, 53 (21.9%) pts experienced a mild RDS which was defined as: troublesome fatigue/itching/bone pain/abdominal discomfort (36 pts, 67.9%); onset of night sweats/fever/weight loss (9 pts, 17%); symptomatic increase of spleen length (16 pts, 30.2%). In 2 additional (0.8%) pts, RDS required hospitalization due to sudden spleen rupture (1 pt) and uncontrolled fever, with dyspnoea, fatigue and weight loss (1 pt), which recovered only after RUX rechallenge. Median time from RUX stop to RDS occurrence was 10 days (2-65).

Factors at RUX stop significantly associated to increased risk of RDS in univariate analysis were: PLT <100 x109/L (HR:2, p=0.02), RUX dose ≤10 mg BID (HR:3.8, p=0.001), spleen length ≥10 cm (HR: 1.8, p=0.03), and discontinuation due to AEs (HR:1.83, p=0.02). In multivariable analysis, RUX dose ≤10 mg (HR:3.4, p=0.01), spleen ≥10 cm (HR: 2.0, p=0.01), and discontinuation due to AEs (HR:1.87, p=0.03) retained statistical significance (Fig.1). Finally, RDS was significantly associated with the need of RUX rechallenge, with 10/55 (18.2%) RDS pts eventually resuming RUX (p<0.001) (Fig.2).

Conclusion

Severe RDS is very rare (<1% of pts), but symptoms and/or splenomegaly significantly increase in >20% of pts after RUX stop. Pts at higher risk for RDS, particularly those whose discontinuation is forced by AEs, should be followed more cautiously. Also, RDS may identify a population that can still benefit from RUX rechallenge because the rebound indicates residual disease control activity (i.e. those suspended intentionally for apparent loss of efficacy). Overall, these results highlight the need for implementation of active prevention strategies and suggest a quick switch to alternative treatment if clinically indicated.

Session topic: 16. Myeloproliferative neoplasms - Clinical

Keyword(s): Myelofibrosis, Ruxolitinib

Abstract: S217

Type: Oral Presentation

Session title: Novel therapies and pitfalls in MPN

Background
Ruxolitinib (RUX) is effective in controlling myelofibrosis (MF)-related splenomegaly and symptoms by JAK1/JAK2 inhibition. In the phase I/II study, 11% of the patients (pts) experienced a RUX discontinuation syndrome (RDS), a wide range of adverse events (AEs) attributed to a rebound cytokine storm.

Aims

To investigate in a real-world contest: 1) incidence, timing and severity of RDS; 2) type of prevention strategies; 3) risk factors associated with RDS.

Methods

Overall, 700 MF pts were treated with RUX in 20 European Hematology Centers. Spleen (SR) and symptoms (SyR) responses were evaluated according to IWG-MRT criteria.

Results

After a median follow-up from RUX start of 36.3 mos, 242 (34.6%) pts stopped RUX and survived >30 days after discontinuation. At RUX start, characteristics of these 242 pts were: median age 67y (24-88); males 59.9%; PMF 59.9%; median Hb 10 g/dl; median PLT/WBC: 211/10.2 x109/l. At any time, 43.8% and 80.2% of pts achieved a SR or a SyR.

Causes of RUX stop were: RUX failure (60.6%: lack/loss of SR/SyR or leukemic transformation); AEs (28.6%; hematological AEs: 20.7%); other causes (10.8%). At the time of decision to stop RUX, daily dose (mg BID) was: 5, 10, 15 or 20 in 46.3%, 21.9%, 16.5% and 15.3% of pts.

An active strategy to prevent RDS was performed in 101 (41.7%) pts, specifically: RUX taper alone (44 pts); RUX taper in combination with prednisone (PDN) ± hydroxyurea (HU) (32 pts); PDN ± HU without tapering (25 pts). Median duration of tapering was 20 days (2-90). Median PDN dose was 12.5 mg/d, with a median exposure of 29 days (10-255); HU was used at a median dose of 1 g/d for a median of 60 days (4-210). In the remaining 141 (58.2%) pts, RUX was quickly discontinued without any specific intervention.

Overall, 53 (21.9%) pts experienced a mild RDS which was defined as: troublesome fatigue/itching/bone pain/abdominal discomfort (36 pts, 67.9%); onset of night sweats/fever/weight loss (9 pts, 17%); symptomatic increase of spleen length (16 pts, 30.2%). In 2 additional (0.8%) pts, RDS required hospitalization due to sudden spleen rupture (1 pt) and uncontrolled fever, with dyspnoea, fatigue and weight loss (1 pt), which recovered only after RUX rechallenge. Median time from RUX stop to RDS occurrence was 10 days (2-65).

Factors at RUX stop significantly associated to increased risk of RDS in univariate analysis were: PLT <100 x109/L (HR:2, p=0.02), RUX dose ≤10 mg BID (HR:3.8, p=0.001), spleen length ≥10 cm (HR: 1.8, p=0.03), and discontinuation due to AEs (HR:1.83, p=0.02). In multivariable analysis, RUX dose ≤10 mg (HR:3.4, p=0.01), spleen ≥10 cm (HR: 2.0, p=0.01), and discontinuation due to AEs (HR:1.87, p=0.03) retained statistical significance (Fig.1). Finally, RDS was significantly associated with the need of RUX rechallenge, with 10/55 (18.2%) RDS pts eventually resuming RUX (p<0.001) (Fig.2).

Conclusion

Severe RDS is very rare (<1% of pts), but symptoms and/or splenomegaly significantly increase in >20% of pts after RUX stop. Pts at higher risk for RDS, particularly those whose discontinuation is forced by AEs, should be followed more cautiously. Also, RDS may identify a population that can still benefit from RUX rechallenge because the rebound indicates residual disease control activity (i.e. those suspended intentionally for apparent loss of efficacy). Overall, these results highlight the need for implementation of active prevention strategies and suggest a quick switch to alternative treatment if clinically indicated.

Session topic: 16. Myeloproliferative neoplasms - Clinical

Keyword(s): Myelofibrosis, Ruxolitinib

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